Ancestry-based differences in the immune system are associated with lupus severity

Abstract Systemic lupus erythematosus (SLE) affects 1 in 537 of African American (AA) women, which is >2-fold more than European American (EA) women. AA patients also develop the disease at a younger age, have more severe symptoms, and a greater chance of early mortality. We used a multi-omics approach to uncover ancestry-specific immune alterations in SLE patients and healthy controls that may contribute to disease disparities. Cell composition, signaling, and epigenetics were evaluated by mass cytometry; droplet-based single cell transcriptomics and paired proteogenomics (scRNA-Seq/scCITE-Seq). Soluble mediator levels were measured in plasma and stimulated whole blood. Toll-like receptor (TLRs) pathways are activated by vaccination and microbial infection, and are also key drivers of autoimmune disease. We observed enhanced TLR3/4/7/8/9-related gene expression in immune cells from AA versus EA SLE patients. TLR7/8/9 and IFNα phospho-signaling responses were heightened even in immune cells from healthy AA versus EA controls. TLR stimulation of healthy AA and EA immune cells recapitulated the distinct ancestry-associated SLE immunophenotypes. Thus, healthy individuals show ancestry-based differences in innate immune pathways that could influence the course and severity of lupus and other diseases.